ClinVar Genomic variation as it relates to human health
NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000528.4(MAN2B1):c.1383C>A (p.Tyr461Ter)
Variation ID: 281152 Accession: VCV000281152.22
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 19p13.13 19: 12657482 (GRCh38) [ NCBI UCSC ] 19: 12768296 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 6, 2016 Apr 15, 2024 Dec 19, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000528.4:c.1383C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000519.2:p.Tyr461Ter nonsense NM_001173498.2:c.1380C>A NP_001166969.1:p.Tyr460Ter nonsense NC_000019.10:g.12657482G>T NC_000019.9:g.12768296G>T NG_008318.1:g.14296C>A - Protein change
- Y461*, Y460*
- Other names
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- Canonical SPDI
- NC_000019.10:12657481:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00001
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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LOC129391064 | - | - | - | GRCh38 | - | 63 |
MAN2B1 | - | - |
GRCh38 GRCh37 |
1534 | 1704 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Dec 19, 2023 | RCV000301281.18 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 7, 2020 | RCV000723878.6 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Dec 11, 2015)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000331576.4
First in ClinVar: Dec 06, 2016 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 3
Sex: mixed
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000410795.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The MAN2B1 c.1383C>A (p.Tyr461Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in a total of … (more)
The MAN2B1 c.1383C>A (p.Tyr461Ter) variant is a stop-gained variant that has been reported in two studies in which it was found in a total of eight individuals with alpha-mannosidosis (including two sibling pairs) in a compound heterozygous state (Stensland et al 2012; Borgwardt et al. 2015). Control data are not available for this variant, which is reported at a frequency of 0.0001525 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is based on one allele only in a region of poor sequence coverage. Due to the potential impact of stop-gained variants and the supporting evidence, the p.Tyr461Ter variant is classified as pathogenic for alpha-mannosidosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Dec 25, 2020)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001468285.1
First in ClinVar: Jan 07, 2021 Last updated: Jan 07, 2021 |
Comment:
Variant summary: MAN2B1 c.1383C>A (p.Tyr461X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: MAN2B1 c.1383C>A (p.Tyr461X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.7e-05 in 172302 control chromosomes. c.1383C>A has been reported in the literature in individuals affected with Alpha-Mannosidosis and subsequently cited by others (example, Riise Stensland_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. One submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Dec 07, 2020)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV001781059.1
First in ClinVar: Aug 13, 2021 Last updated: Aug 13, 2021 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 26048034, 22161967, 17979865) (less)
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Pathogenic
(Sep 05, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002014364.1
First in ClinVar: Nov 12, 2021 Last updated: Nov 12, 2021 |
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Pathogenic
(Mar 25, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
unknown
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Baylor Genetics
Accession: SCV004191898.1
First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023 |
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Pathogenic
(Dec 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002246670.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Tyr461*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Tyr461*) in the MAN2B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MAN2B1 are known to be pathogenic (PMID: 9915946, 22161967). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with alpha-mannosidosis (PMID: 22161967). ClinVar contains an entry for this variant (Variation ID: 281152). For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Apr 09, 2021)
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criteria provided, single submitter
Method: clinical testing
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Deficiency of alpha-mannosidase
Affected status: unknown
Allele origin:
germline
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Molecular Genetics, Royal Melbourne Hospital
Additional submitter:
Shariant Australia, Australian Genomics
Accession: SCV002503619.2
First in ClinVar: Apr 27, 2022 Last updated: Apr 15, 2024 |
Comment:
This sequence change creates a premature termination codon at position 461 in exon 11 (of 24) of MAN2B1 (p.(Tyr461*)). It is expected to result in … (more)
This sequence change creates a premature termination codon at position 461 in exon 11 (of 24) of MAN2B1 (p.(Tyr461*)). It is expected to result in nonsense mediated decay, in a gene where loss of function is an established mechanism of disease (ClinGen). The variant is present in a large population cohort at a frequency of 0.002% (3/172,302 alleles, 0 homozygotes in gnomAD v2.1), but this is based on three alleles in a region of poor coverage. It has been reported in multiple individuals with alpha-mannosidosis with a second pathogenic allele, and segregates with the condition in at least one family (PMID: 22161967, 26048034). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.1, this variant is classified as PATHOGENIC. Following criteria are met: PVS1, PM3_Strong, PP1. (less)
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Pathogenic
(May 08, 2020)
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no assertion criteria provided
Method: clinical testing
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Alpha-mannosidosis
Affected status: unknown
Allele origin:
germline
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Natera, Inc.
Accession: SCV002086932.1
First in ClinVar: Apr 23, 2022 Last updated: Apr 23, 2022 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation. | Posey JE | The New England journal of medicine | 2017 | PMID: 27959697 |
Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. | Borgwardt L | Orphanet journal of rare diseases | 2015 | PMID: 26048034 |
Identification of 83 novel alpha-mannosidosis-associated sequence variants: functional analysis of MAN2B1 missense mutations. | Riise Stensland HM | Human mutation | 2012 | PMID: 22161967 |
Spectrum of mutations in alpha-mannosidosis. | Berg T | American journal of human genetics | 1999 | PMID: 9915946 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=MAN2B1 | - | - | - | - |
Text-mined citations for rs775200333 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.